A genome‐wide association study in Caucasian women suggests the involvement of HLA genes in the severity of facial solar lentigines

Abstract

Solar lentigines are a common feature of sun-induced skin ageing. Little is known, however, about the genetic factors contributing to their development. In this genome-wide association study, we aimed to identify genetic loci associated with solar lentigines on the face in 502 middle-aged French women. Nine SNPs, gathered in two independent blocks on chromosome 6, exhibited a false discovery rate below 25% when looking for associations with the facial lentigine score. The first block, in the 6p22 region, corresponded to intergenic SNPs and also exhibited a significant association with forehead lentigines (P = 1.37 × 10(-8) ). The second block, within the 6p21 HLA region, was associated with decreased HLA-C expression according to several eQTL databases. Interestingly, these SNPs were also in high linkage disequilibrium with the HLA-C*0701 allele (r(2) = 0.95). We replicated an association recently found by GWAS in the IRF4 gene. Finally, a complementary study on 44 selected candidate SNPs revealed novel associations in the MITF gene. Overall, our results point to several mechanisms involved in the severity of facial lentigines, including HLA/immunity and the melanogenesis pathway.

Genome-Wide Association Shows that Pigmentation Genes Play a Role in Skin Aging

“…In addition to BG6, a number of other skin aging-related traits have been analyzed by GWAS (Chang et al, 2014;Jacobs et al, 2015aJacobs et al, , 2015bLaville et al, 2016;Le Clerc et al, 2013;Liu et al, 2016). Supplementary Table S3 online summarizes the BG6 association for those SNPs previously reported as reaching genome-wide significance with other skin aging-related traits.…”

“…These include perceived facial age (Liu et al, 2016), facial photoaging (Le Clerc et al, 2013), and the combined impact of intrinsic and extrinsic factors on facial aging (Chang et al, 2014). Additional GWASs have been conducted on traits related to photoaging such as actinic keratosis and facial pigmented spots (Jacobs et al, 2015a(Jacobs et al, , 2015bLaville et al, 2016). Together, these have identified genetic variants on chromosomes 3, 6, 16, 20, and X.…”

Genetic variation in IRF4 expression modulates growth characteristics, tyrosinase expression and interferon‐gamma response in melanocytic cells

“…Using primary MB strains homozygous for C/C and T/T IRF4 genotypes, we observed a positive correlation between higher IRF4 expression levels directed by the rs12203592*C allele with endogenous TYR levels, a finding further supported by reduction in TYR levels following IRF4 knock‐down in primary melanocytic cells. Higher TYR expression matched a higher activity based on the L‐DOPA oxidation assays and can potentially explain the basis of rs12203592*T allele association with lighter pigmentation traits (Duffy, Zhao, et al., ; Praetorius et al., ), solar lentigines (SL) (Laville et al., ) and skin ageing (Law et al., ) as a consequence of lower IRF4 expression in this context. Together these data corroborate earlier reports of synergy between MITF and IRF4 in regulating TYR expression (Praetorius et al., ; Visser et al., ) and reveals that this regulation also extends to less differentiated melanoblast cells.…”

A genome wide association study identifies new genes potentially associated with eyelid sagging

“…Many reasons may explain the non‐replication of both signals. These reasons primarily include study power since our cohort has a relatively small sample size and limited power, of approximately 35% to identify SNPs explaining modest fraction of the phenotype, as mentioned in our previous study, but also differences between cohorts such as cohort origin and gender distribution. Indeed, Jacobs et al have underlined a different risk of sagging eyelid between the two genders suggesting potential sex‐specific genetic factors .…”

“…Indeed, Jacobs et al have underlined a different risk of sagging eyelid between the two genders suggesting potential sex‐specific genetic factors . All these reasons have been extensively discussed in a recently published correspondence . To limit these issues, a great attention was given to the phenotyping method because techniques to assess eyelid sagging could impact the power of the analysis, as discussed by Jacobs et al .…”